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PDBsum entry 1a7c
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Hydrolase inhibitor/peptide
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PDB id
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1a7c
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Interfering with the inhibitory mechanism of serpins: crystal structure of a complex formed between cleaved plasminogen activator inhibitor type 1 and a reactive-Centre loop peptide.
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Authors
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Y.Xue,
P.Björquist,
T.Inghardt,
M.Linschoten,
D.Musil,
L.Sjölin,
J.Deinum.
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Ref.
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Structure, 1998,
6,
627-636.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) is an important
endogenous regulator of the fibrinolytic system. Reduction of PAI-1 activity has
been shown to enhance dissolution of blood clots. Like other serpins, PAI-1
binds covalently to a target serine protease, thereby irreversibly inactivating
the enzyme. During this process the exposed reactive-centre loop of PAI-1 is
believed to undergo a conformational change becoming inserted into beta sheet A
of the serpin. Incubation with peptides from the reactive-centre loop transform
serpins into a substrate for their target protease. It has been hypothesised
that these peptides bind to beta sheet A, thereby hindering the conformational
rearrangement leading to loop insertion and formation of the stable
serpin-protease complex. RESULTS: We report here the 1.95 A X-ray crystal
structure of a complex of a glycosylated mutant of PAI-1, PAI-1-ala335Glu, with
two molecules of the inhibitory reactive-centre loop peptide N-Ac-TVASS-NH2.
Both bound peptide molecules are located between beta strands 3A and 5A of the
serpin. The binding kinetics of the peptide inhibitor to immobilised
PAI-1-Ala335Glu, as monitored by surface plasmon resonance, is consistent with
there being two different binding sites. CONCLUSIONS: This is the first reported
crystal structure of a complex formed between a serpin and a serpin inhibitor.
The localisation of the inhibitory peptide in the complex strongly supports the
theory that molecules binding in the space between beta strands 3A and 5A of a
serpin are able to prevent insertion of the reactive-centre loop into beta sheet
A, thereby abolishing the ability of the serpin to irreversibly inactivate its
target enzyme. The characterisation of the two binding sites for the peptide
inhibitor provides a solid foundation for computer-aided design of novel, low
molecular weight PAI-1 inhibitors.
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Figure 1.
Figure 1. The structures of latent and active PAI-1. (a)
Schematic model of latent PAI-1 [17] and (b) a constructed model
of active PAI-1 [16] based on the structures of both latent
PAI-1 and antithrombin III [38] with some important structural
domains indicated. The protein is shown from the front with the
b sheet A coloured red; b strands 3A to 5A are indicated. (The
figure was prepared using the program MOLSCRIPT [39].)
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1998,
6,
627-636)
copyright 1998.
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